May, 1946
Benzal group
(1) Benzal (2) o-Chlorobenzal (3) o-Methoxybenzal (4) p-Methoxybenzal (5) p-Dimethylaminobenzal
NOTES
909
TABLE I ANILSFROM 1.1-DIETHYLAMINO-4-AMINOPENTANE B. P., Yield, Analyseo, % ’ N OC. Mm. % X*D SP. g.%O Formula Calcd. Found 148-150 2.5 67 1.5134 0.9087 CI&IZBNZ 11.38 11.36 150-151 3.0 72 1.5225 .9989 CieHzsNzCl 10.00 10.17 154-155 3.0 80 1.5210 CliHz80Nz .9558 10.14 10.38 153-154 3.0 76 1.5250 C I , H ~ ~ O N ~ 10.14 .95% 10.32 193-194 3.0 64 1.558 C18HnlNs 14.53 14.54 .9450
This compound has a chlorophenyl group in place mental avian malaria: benzal-m-bromoaniline, benzal-pm-bromobenzal-aniline, benzal-o-hydroxyof the fuzed chlorobenzo group in atebrin. Later2 bromoaniline, P-dimethylaminoaniline, benzal-p-dimethylaminoaniline, i t was shown that another related model, 2-(3’- 1m:zalaniline and p-dimethylaminobenzal-o-methoxyanilchloropheny1)-4-[ (a-methyl-29-diethylaminobuty1)- ii:e,4 amino]-6-methylquinoline, was also active. Acknowledgment.-The authors are grateful The principle involved was then extended so t o Drs. R. J. Porter and L. T . Coggeshall, of the that the simple central pyridine nucleus of atebrin University of Michigan, for the antimalarial tests, was used as a fundamental g r ~ u p i n g . ~Among the results of which will be published elsewhere. the compounds examined was Z-(p-y-diethylami(4) The last three compounds were supplied by Merrill Speeter. nopropylaminop1ienyl)-pyridine which was shown See, Gilman, Tolman, Yeoman, Woods, Shirley and Avakian, THIS to be active in experimental avian malaria. JOURNAL, 88, 426 (1946), on N-(m-trifluoromethylbenza1)-m-trlA logical extension from the fuzed trinuclear fluoromethylaniline and 4-(m-trifluoromethylbenzalamino)-dibenzosystem of atebrin, t o the fuzed dinuclear system of furan which were also found to be inactive. LABORATORY quinoline, to the simple pyridine nucleus was to CHEMICAL IOWASTATECOLLEGE some appropriately substituted anils having the AMES, IOWA RECEIVED FEBRUARY 23, 1946 azomethine grouping which is present in the aforementioned nitrogen heterocycles. Several anils were prepared in accordance with the typical reThe Methylation of Carvacrylamine action BY JOHN F. R. KUCKAND J. V. KARABINOS H I The preparation and physical constants of p-CH30CsHdCHO 4- CHaC(CHz)aN(CzHs)z + carvacrylamine as well as its N-methylated I derivatives are reported in this communication. NHz Carvacrylamine was obtained by the nitration H H of p-cymene according t o the method of Kobe and I I P-CH~OC~HIC=N--C(CHZ)~N(CZH~)~ Doumani, and catalytic reduction of the 2-nitroI p-cymenea2 Purification was accomplished by CHa recrystallization of the formyl derivative from hot None of these compounds was found active. water and regeneration of the free base. An attempt t o make the N-methyl derivative Experimental by reductive alkylation3gave a mixture of amines. Anils Derived from l,l-Diethylamino-4-amhopentane. Careful vacuum fractionation gave a 15y0yield -Equimolecular quantities of the amine and the aldehyde of the pure tertiary amine which boils slightly were dissolved and mixed in benzene. The reaction was usually instantaneous, the mixture becoming warm and lower than the other two. Other methods for monomethylation were tried. turbid, but in the case of the p-methoxy- and the 9-dimethylamino- derivatives it was desirable to apply heat Methylation of N-formyl-N-carvacryl sodamide to start the reaction. The mixture was allowed to stand in dry toluene with dimethyl sulfate gave a low for ten to fourteen hours, the water was separated, and the benzene layer dried over anhydrous sodium sulfate. The yield of fairly pure secondary amine, and autosolvent was removed by distillation and the product dis- claving 2-bromo-p-cymene with aqueous methyltilled under reduced pressure. The benzaldehyde deriva- amine in the presence of cuprous chloride a t 600 tive was a colorless liquid, and the other compounds were lb./sq. in. max. and 150 to 1 7 5 O gave the Nyellow liquids. 5-( p-Anisalamin0)-8-methylquinoline.-( By Fred J. m e q y l derivative in 25% yielz. All methods Marshall). A mixture of 4.7 g. (0.03 mole) of 5-amino-8- attempted in this Laboratory for alkylating the methylquinoline and 4 g. (0.03 mole) of p-anisaldehyde in amine directly gave a mixture of amines from 35 cc. of benzene was refluxed for three and one-half hours. which the pure secondary amine could be sepaAfter removal of the benzene under reduced pressure, the product was crystallized from methanol. The yield was rated by a nitrosation procedure.q 5.7 g. (68%) of compound melting a t 102-104”. Anal. Calcd. for ClsHleONz: N, 10.14. Found: N, 10.37. I n . addition t o the compounds described, the following were also examined and found to be inactive in experi(2) Gilman, Chrislian and Spatz, ibid., 68, in press (1946). (3) Giman and Edward, ibid., 68, in press (1946).
(1) K. A. Kobe and T. F. Doumani, “Organic Syntheses,” Vol. 21, John Wiley and Sons, Inc., New York, N. Y.,1941, p. 96. (2) C. F. H. Allen and J. Van Allan, “Organic Syntheses,” Vol. 22, 1942, p. 9. (3) W. S. Emerson and H. W. Mohrman, THISJOURNAL, 69, 69 (1940). (4) J . S. Buck and C. S. Ferry, “Organic Syntheses,” Coll. Vol. 2, John Wiley and Sons. Inc., New York, N. Y., 1943, p. 290.
NOTES
910
The physical constants of the three amines as well as some derivatives are listed below. TABLE I PHYSICAL CONSTANTS
THEIR
B. p., 'C. 1Z2zD
CARVACRYLAMINES DERIVATIVES
O F THE
AND
N.N-
Carvacrylamine
N-Methyl-
Dimethyl-
242 1.5402 0.9403"
236 1.5363 0.9325
84 (5 mm.) 1.5131 0.9028
dl'r Oxalate M. p., OC. 149-15ob 114-115' 132-133 Phenylthiourea M. p.. "C. 117 95-96 ... a F. W. Semmler, Ber., 25, 3352 (1892), reported 0 9442 but this was recorded in Beilstein as 0.9942. R . G. Cooke and A . K. Matbeth, J . Chem. Soc., 1593 (1937) reported m. p. of 150 . Apparently an acid salt, unstable on standing. May also be dehydrated.
..
VOl. 68
and ethyl alcohols as solvents in order to eliminate the necessity of preparing powdered sodium, sodamide or alcohol-free sodium ethylate. We found that reactions could be carried out more quickly, the yields were good, and the direction of ring closure not affected. Ethyl-/3~carbomethoxyethylthioglycolate was cyclized at 0' in four ways, the ureides prepared and their melting points compared with those of known ureides.' (A) Sodium methylate in ether: The major product was 2-carbomethoxythiophan-3-one (oil, b. p. -102.5-105O [5-6 mm.]). Anal. calcd. for C6Hs03S; C, 44.99; H, 5.03. Found: C, 45.76; H,5.15. Ureide, in. p. 2221-222'. (B) Sodium methylate in methyl alcohol gave the same product as (A). Anal. Found: C, 45.08; H, 5.16. Ureide, m. p. 222'. (C) Sodium ethylate in ether gave 2-carbethoxythiophan-3-one (oil, b. p. 98-101O [3-4 mm.]). Anal. calcd. for C7H1003S; C, 48.26; H, 5.79; Found: C, 48.09; H, 5.68. Ureide, m. p. 171172'. (D) Sodium ethylate in ethyl alcohol gave the same product as (C). Found: C, 48.00; H, 5.80. Ureide, m. p. 172'. In all cases the 2-carbalkoxythiophan-3-one was the main product formed. Methyl and ethyl alcohols are suitable solvents for this ring closure if one keeps in mind the possibility of ester exchange such as occurred to a large extent in (A) and completely in (B).
Anal. Calcd. for N-methvl carvacrvlamine acid oxalate hydrate, C101113NHCH3.C2HiOd.H10: -C, 57.53; H, 7.80; K, 517. Found: C, 57.72; H, 7.55; N, 5.12, 5.38. .I nul. Cakd. for N,N-dimethyl carvacrylamine oxalate, (CioH13~C;Hs)E,C1HE0a.Hr0: subs. 0.2G.52 g., 0.1340 g.; 0.09661 N KOH, 20.35 ml., 10.34 ml. Found: 20.48 ml., 10 34 mi. Anal. Calcd. for carvacrylamine, CloN15N: N, 9.39. Found: N. 9.16. A n d . Calcd. for N-methvlcarvacrvlamine.. CIIH17N: .. .. N, 8.59. Found: N, 8.65, 8.?0. Anal. Calcd. for N,N-dimethylcarvacrylamine, C,?H , Q S : S, 7.91. Found: N, 7.78, 7.82. Anal. Calcd. for carvacrvlamine Dhenvlthiourea. C,,HmSzS: C, 71.78; H, 7.09. -Found:*C, f1.75; H, 7 . 0 ~ . ' Anal. Calcd. for N-methylcarvacrylamine phenylthiourea, C18HteN2S: C, 72.45; H, 7.43. Found: C. ABBOTT LAUORATORIES 72.36; H , 7.04. SORTH CHICAGO, ILLISOIS AIRCRAFT ENGINERESEARCH LABORATORY NATIONAL ADVISORY COMMITTEE FOR AERONAUTICS CLEVELAND, OHIO RECEIVEDJANUARY 23, 194ti
RECEIVI'LI APRIL 4, 1946
6-Methoxy-%amino- 1,2,3,4-tetrahydroquinoline
Carbalkoxythiophanones B Y EDMOVD E. MOOREAND MARJORIE B. MOORE
Several reports on the direction of the ring closure of dialkyl esters of P-carboxyethylthioglycolic acid have appeared in the recent literat~re.1,%3.4. Using sodium in benzene Karrer and Schmidl and Buchman and Cohen2 reported that the main product formed was 4-carbalkoxythiophan3-one. Woodward and Eastman3 using sodium methoxide in ether reported that a t low temperatures the main product was 2-carbalkoxythiophan-3-one while a t high temperatures (110') sodium methoxide in toluene gave mostly 4carbalkoxythiophan-3-one. Avison, et aLI4 reported that sodium in benzene gave 2-carbalkoxyt hiophan-3-one. During the course of some work on ring closures of this type, we investigated the use of methyl (1) K a n e r and Schmid, Helu. Chrm. Acfo, 2 1 , 124 (1944). (2) Biichman and Cohen. THISJOURNAL, 66, 847 (1944). (3) Woodward and Eastrnan, i b i d . , 66, 849 (1944). (4) Avison, Bergel, Cohen and Haworth, Nofure, 164, 459 (1944).
BY CHARLESC. PRICE^
AND
HARRYI;. HERFRANDSON
Although Balaban3 has reported the successful and 5reduction of 5-amino-6-methoxyquinoline amino-8-methoxyquinolineto the tetrahydro analogs by the action of tin and hydrochloric acid, Gmethoxy-8-aminoquinoline was reported to form an intensely purple solution from which the tetrahydroquinoline was not isolated. We have experienced no difficulty in isolating the product in good yield, either from tin and hydrochloric acid reduction or catalytic hydrogenation. The product is easily oxidizable and discolors on exposure to air. It was characterized as the picrate and by conversion to the imidazole. 8-Amino-6-methoxy-l,2,,3,4-tetrahydroquinolineHydrochloride.-To 3.5 g. (0.02 mole) of distilled 8-amino-6(1) T h e work reported in this note was carried out under a con. tract, recommended by t h e Committee o n Medical Research, be tween t h e O 5 c e of Scientific Research and Development and t h e University of Illinois. (2) Present address: Department of Chemistry, University of Notre Dame, Notre Dame, Indiana. (3) Balaban, J . Chem. SOC.,2624 (1932).
